In 1968, Alain Carpentier first introduced the use of glutaraldehyde (“Glut”) to treat animal tissues before implantation, leading to the first implantation of a valvular bioprosthesis in man. Carpentier, A. et al., J Thorac Cardiovasc Surg. 1969 October; 58 (4): 467-83. In the following years the process was improved, and the valve was mounted into a stent leading to the concept of a bioprosthesis. Carpentier, A. Med Instrum. 1977; 11 (2): 98-101.
As experience grew several limitations became apparent, including tissue calcification and collagen degeneration. Calcium mitigation was obtained by adding a surfactant and ethanol to the glutaraldehyde process. Carpentier A., Nashef A. et al. Circulation 70 (3Pt2): 1165-68; and intensively described in U.S. Pat. No. 4,885,005 Improved glutaraldehyde fixation was obtained by immersing the tissue in a heated glutaraldehyde solution, preferably at a temperature of about 45 to 55° C. for a period of time ranging from 10 to 12 days, according to the method first proposed by Carpentier S. et al., Ann. Thorac. Surg. Dec. 66 (6 Suppl.) 3264-6, which is incorporated herein in its entirety.
Although these techniques have proven to be efficient in reducing tissue calcification and enhancing tissue stability, there remains a need for further improvements, in particular to enlarge the use of valvular bioprosthesis in young patients.
Diamines, including lysine or Jeffamine, have been proposed by others to crosslink free aldehyde groups in bioprosthetic tissues. Jeffamine®, sold by Huntsman International, was first used by Hendricks et al (U.S. Pat. No. 6,166,184 and U.S. Pat. No. 7,053,051) to avoid treating the tissue with glutaraldehyde, which was said to enhance calcification. The drawbacks in these methods are that amino groups from adjacent collagen molecules and residual amino groups from the diamines were not crosslinked or further modified. As a result, tissue stability was compromised. Thus, there remains a need for improved bioprosthetic tissue with enhanced post-implantation durability.